Geriatic patients exhibit a high incidence of toxic drug effects. This may be caused by decreases in hepatic drug-metabolizing enzymes. Information concerning the effect of aging on drug metabolism is needed for the recommendation of types and dosages of drugs suitable for use in the elderly. Biotransformation of drugs and foreign chemicals occurs via the microsomal electron transport system, which consists of cytochrome P-450 (in multiple forms), NADPH-cytochrome P-450 reductase, and phosphatidyl choline. The proposed research will investigate age-related alterations in this system, using liver microsomes prepared from young-adult (3-month), middle-aged (l6-month) and sensecent rats (29-month) (Fischer 344, males). Decreases in drug-metabolism activities will be correlated with qualitative or quantitiative changes in microsomal electron transport components. Reconstitution experiments will determine which component is critical and rate-limiting for the maintenance of microsomal drug-oxidation reactions in aging animals. The hypothesis that aging modification may involve changes in the quantity of individual forms of cytochrome P-450 will be examined. The effect of aging onan animal's ability to increase drug-metabolism reactions in response to environmental stimuli will be investigated. Inducing agents (phenobarbital, 3-methylcholanthrene and testosterone) will be administered to rats in each of the three age groups and their effects on the various parameters of drug metabolism will be determined. The proposed research would be the first to examine aging modification of drug metabolism at a molecular level. Baseline information for future investigation into underlying biochemical mechanisms will be sought.